BACKGROUND AND PURPOSE - It remains unclear whether C-reactive protein (CRP) is a serum marker for atherothrombotic disease or a causal factor in the pathogenesis of atherosclerosis. We explored the association between CRP gene variations and cerebral small-vessel disease (SVD) in the Rotterdam Scan Study (N=1035) and the MEMO Study (N=268). METHODS - Common haplotypes within the CRP gene were determined by genotype-tagging single-nucleotide polymorphisms. Then their relation with periventricular and subcortical white matter lesions and the prevalence of lacunar brain infarcts was explored by regression analyses. RESULTS - There was no association between CRP haplotypes and measures of cerebral SVD in either study. There was no effect modification of the association between serum CRP levels and measures of SVD by CRP haplotypes. CONCLUSIONS - Our observations suggest that CRP is not causally involved in the pathogenesis of SVD.